Acta Derm Venereol 2013; 93: 131–137

REVIEW ARTICLE

A Comprehensive Pathophysiology of Dandruff and Seborrheic

Dermatitis – Towards a More Precise Definition of Scalp Health
James R. Schwartz1*, Andrew G. Messenger2, Antonella Tosti3, Gail Todd4, Maria Hordinsky5, Roderick J. Hay6,
Xuemin Wang7, Claus Zachariae8, Kathy M. Kerr1, James P. Henry1, Rene C. Rust9 and Michael K. Robinson1
1
The Procter & Gamble Company, Cincinnati, USA, 2Department of Dermatology, Royal Hallamshire Hospital, Sheffield, UK, 3Department of Dermatology
& Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA, 4Division of Dermatology, Groote Schuur Hospital, University of
Cape Town, Cape Town, South Africa, 5Department of Dermatology, University of Minnesota, Minneapolis, Minnesota, USA, 6Infectious Disease Clinic,
Dermatology Department, Kings College Hospital NHS Trust, Denmark Hill, London, United Kingdom, 7Shanghai Skin Disease Hospital, Shanghai, China,
8
Department of Dermatology, Gentofte University Hospital, Copenhagen, Denmark, and 9The Procter & Gamble Company, Darmstadt, Germany

Despite an increasing knowledge of dandruff and se-
borrheic dermatitis (D/SD), the pathophysiological
understanding is still incomplete but suggests a role of
Malassezia yeasts in triggering inflammatory and hy-
per-proliferative epidermal responses. The objective of
this report is to review published literature from in vivo
studies of D/SD populations to provide a more complete
description of overall scalp health. New biomolecular
capabilities establish a depth of pathophysiological un-
derstanding not previously achievable with traditional
means of investigation. Biomarkers representing inflam-
mation, hyper-proliferation and barrier function are
all perturbed by the D/SD condition and robustly re-
spond to therapeutic resolution. These biomarkers can
be sampled noninvasively, enabling their use in routine
clinical evaluations as either surrogate endpoints or com-
plementary ones to classical signs/symptoms to broaden
the etiological learning. Key words: dandruff; seborrheic
dermatitis; inflammation; hyper-proliferation; skin bar-
rier; biomarkers; scalp health.
Accepted Mar 12, 2012; Epub ahead of print Aug 8, 2012
Acta Derm Venereol 2013; 93: 131–137.
Dr James R. Schwartz, Procter & Gamble Company, Cin-
cinnati, USA. E-mail: schwartz.jr.2@pg.com
Dandruff and seborrheic dermatitis (D/SD) are common
afflictions of the human scalp (1) and considered the same
basic condition differing only in magnitude (2). Heredity
plays only a small role in developing a predisposition for
the condition (3). A comprehensive review of the pathop-
hysiological changes in the stratum corneum (SC) in these
conditions at the macro (signs and symptoms), micro (phy-
siological structure and function) and biomolecular strata
may enable a precise and more complete determination of
the condition of the scalp and also the therapeutic responses
to treatment leading to restoration of homeostasis. A more
complete description of the pathophysiology of the D/SD
condition results from combining these 3 informational
strata. This combination can lead to a paradigm shift in
describing what constitutes a return to “scalp health.”
© 2013 The Authors. doi: 10.2340/00015555-1382
Journal Compilation © 2013 Acta Dermato-Venereologica. ISSN 0001-5555
A more comprehensive description of “scalp health“
incorporating new biomolecular markers in addition to the
existing clinical parameters has several benefits: (i) Advan-
ces the understanding of the biopathology of the condition;
(ii) Provides a framework to assess the thoroughness of
therapies; (iii) Enables the use of other clinical endpoints
in addition to the commonly observed signs and symp-
toms; and (iv) Establishes relevant sub-clinical parameters
that can supplement clinical observations.
In order to discuss the characteristic structural and
biomolecular abnormalities associated with D/SD, it
is convenient to categorize them by the following 4
sequential pathophysiological phases (4):
• Malassezia ecosystem and interaction with the
epidermis;
• Initiation and propagation of inflammation;
• Disruption of proliferation and differentiation
processes of the epidermis; and
• Physical and functional skin barrier disruption.
Each pathophysiological phase can then be considered
sequentially at the 3 informational strata, progressing
from macro to micro perspective, viz. Symptoms and
signs; Structure and function, and Biomolecular changes,
focusing almost exclusively on in vivo observations on
D/SD populations to assure the relevance to the clinical
condition (see supplementary Appendix for Material and
Methods; available from http://www.medicaljournals.se/
acta/content/?doi=10.2340/00015555-1382).
The 4 pathophysiological phases and the 3 informational
strata can be considered orthogonal views of the total D/
SD data. By combining these views, an organizational
model emerges (Fig. 1) which allows each independent
measure to be categorized by its pathophysiological phase
and informational stratum. This categorization facilitates
the comparison of measures within a given phase and
across the strata or vice versa. A more complete model
of scalp health emerges, including the circular nature of
the pathophysiology, in which decreased barrier integrity
increases further susceptibility.
In this review, each informational stratum will be co-
vered sequentially, starting with the macro level observa-
tions and finishing at the foundational biomolecular level,
Acta Derm Venereol 93
132 J. R. Schwartz et al.
Fig. 1. Chart summarizing the measures of dandruff and seborrheic dermatitis arranged by the pathophysiological phase and informational stratum showing
a more complete model for scalp health.
representing an increasing level of depth in analysis from
superficial/optical, to fundamental/physiological.
Initially, the focus will be on differences between D/
SD and normal populations to enable a comprehensive
description of the D/SD condition and its pathophysiolo-
gical foundations. Finally, the available therapeutic data
will be reviewed, allowing a determination of which
measurements represent useful clinical parameters to
evaluate treatment effectiveness more accurately than
possible with traditional approaches.
Signs and symptoms of dandruff and
seborrheic dermatitis
The predominant and hallmark signs and symptoms
are, respectively, flaking and pruritus, which tend to
correlate with each other in intensity (4). The quanti-
fication of flakes has generally relied on assessments
by expert graders involving various grading schemes
within blinded studies, but can also be measured in-
strumentally (5). Assessment of pruritus is inherently
subjective and generally involves subjects’ marking
of various types of graduated severity scales (6).
Erythema can occasionally accompany D and more
commonly SD and, like flake assessments, can be as-
sessed by expert graders or optical instruments (7). The
symptom of scalp dryness, which can be manifested
Acta Derm Venereol 93
as the sensation of tightness, originates in impaired
stratum corneum barrier function. Skin dryness sign is
most frequently evaluated by a range of skin surface
electrical property-based instruments or inferred by
measurement of the rate of transepidermal water loss
(TEWL); assessment of tightness typically relies on
subjective self-assessment scores.
Malassezia are commensal scalp yeasts (8) that are
generally regarded as an etiological factor in D/SD (9).
An empirical piece of support for their pathogenicity is
that known therapeutic materials are chemically diverse
but have in common the property of potent anti-fungal
activity (10). Also, it is generally accepted that effective
therapies reduce the Malassezia load from the pre-
treatment level and that re-colonization of Malassezia
post-treatment results in reoccurrence of the condition
(11–15). A potential etiopathological mechanism (16)
involves the lipolytic release of the fatty acid moie-
ties from the parent sebaceous triglycerides by lipase
activity originating from secreted Malassezia lipases
(17); free fatty acids, especially unsaturated ones, can
induce the inflammation and hyperproliferation (16)
known to be components of D/SD leading to the com-
monly observed signs and symptoms associated with
the conditions.
One sign/symptom associated with D/SD that has
only recently been described is that some properties of

the hair fibers on the scalp can be negatively impacted
by the poor scalp skin physiology associated with D/SD
(paralleling similar observations for scalp psoriasis). For
example, comparison of the hairs from D/SD and normal
populations demonstrated D/SD-derived hair to be more
narrow, with a more brittle surface and less shine (18,
19). D/SD can also contribute to increased rates of hair
loss (4, 20), which may be directly due to the presence
of Malassezia (20, 21); anti-dandruff shampoos with
anti-fungal actives appear to reduce hair loss even in
androgenic alopecia populations (22, 23), further sup-
porting a potential involvement of Malassezia.
Therapeutic considerations. Therapeutic resolution of
the signs and symptoms of D/SD has been the traditional
focus of clinical studies. Published studies following
traditional measures of resolution (most commonly
expert-assessed flake appearance) are summarized in a
review (1) that covers efficacy achieved by the common
active materials such as zinc pyrithione (ZPT), ketoco-
nazole and other azoles, selenium sulfide and piroctone
olamine. Since this data is commonly available and
recently reviewed, it will not be reiterated here.
The impact on the structure and
function of epidermis
The outward manifestations of D/SD discussed above
are the result of epidermal structural and functional
disruption. From a structural point of view, while
surface Malassezia are present on all individuals, they
are seen within the layers of the SC of D/SD sufferers
(5, 24, 25). These yeast cells appear to be closely as-
sociated with flakes and parakeratotic cells (26). The
persistence of these parakeratotic (partially nucleated)
cells in the upper SC appears to be a common structural
feature of these conditions (25, 27–29); the quantity
correlates with flaking severity (4). The parakeratotic
cells are likely due to the hyper-proliferative nature
of the epidermis in D/SD, which is evident by an
increased turnover rate (27) and thicker epidermis
(30). The corneocyte envelope structure has also been
observed (24) to be irregular and highly invaginated
due to the lack of synchronization between prolifera-
tion and differentiation in D/SD. These changes are
reflected in irregular moisture-holding capacity and
protein compositions of superficial skin samplings from
dandruff-suffers (31).
In addition to the cellular structure alterations, the
epidermal lipids are affected by D/SD. The characteris-
tic lamellar structure formed by ceramides is replaced
with a much wider, unstructured lipid material (24, 25);
there are also lipid droplets of undetermined origin or
composition within the cellular cytoplasm. Typically,
the sebaceous lipids are altered: free fatty acids are
released by Malassezia-derived lipase activity (in vitro
incubation (17)) and these fatty acids form the basis for
Dandruff and seborrheic dermatitis 133
generation of lipid peroxides (27), which may represent
the primary initiators of inflammation.
At the cellular level, evidence for inflammatory acti-
vity includes leukocytic infiltration in D/SD (32). More
recently, there has been a more extensive histological
cataloging of inflammatory cells, including various
MHC+ lymphoid and NK cells (33). Subtle neutrophil
infiltration into dandruff lesions has also been reported
(34) and neutrophil chemotaxis via anaphylatoxins
derived from the dandruff scales. Recent histologic
analysis has shown such evidence of mild inflammation
(perivascular lymphocytes) in dandruff lesions (30).
These structural variations at the cellular level result
in a SC barrier that is functionally impaired. The bar-
rier is no longer as effective as normal skin at reducing
moisture vapor transmission (35) nor is it as effective at
reducing the penetration of exogenous materials, such
as topical application of a solution containing histamine
(36). This impaired barrier function leads to acceleration
of the condition progression, likely disposing the skin
to be less effective at blocking the penetration of the
inflammatory initiators originating from Malassezia
metabolic activity.
Therapeutic considerations. Effective therapeutic D/SD
treatments not only alleviate the signs and symptoms of
the condition, but result in normalization of the structure
and function of the skin as well. For example, the struc-
tural abnormalities previously associated with hyper-
proliferation (parakeratosis, poorly formed corneocyte
envelope, Malassezia infiltration and lack of epidermal
lipid structure) all are significantly improved after use of
a shampoo containing potentiated ZPT (24). As expected,
function follows structure and, as the structure improves
due to treatment, so does the function of the skin. Barrier
structural integrity as assessed by corneosurfammetry
improves (37) as does a normalization of TEWL (35).
Biomolecular changes
Quantification of molecular level data from the epi-
dermis represents a recently developed capability that
was enabled by new molecular techniques that have
become reliable and reproducible. By comparison of
D/SD and normal populations, such data not only pro-
vide etio­pathological details previously unavailable,
noninvasive approaches also greatly facilitate the eva-
luation of therapeutic benefits of treatments. Initial work
within this context focused on inflammatory mediator
molecules using traditional punch biopsy samples and
immunohistochemistry (33). Using these techniques,
elevated levels of the following cytokines were obser-
ved from D/SD lesions: IL-1α, IL-1β, IL-2, IL-4, IL-6,
IL-10, IL-12, TNF-α and IFN-γ vs. skin from normal
volunteers. Also non-lesional skin from D/SD subjects
had elevated levels of these cytokines vs. normal skin.
These data provided an early indication that D/SD might
Acta Derm Venereol 93
134 J. R. Schwartz et al.

be differentiated from the norm at a molecular level (and observations (36) and likely part of the reason for the
provided further support that these conditions have an decreased skin barrier function.
inflammatory component). Subsequent improvements Based on the availability of these new non-invasive
in methodology were developed using non-invasive sampling methods as well as bio-analytical capabilities,
skin surface sampling methodologies combined with other relevant biomarkers of the D/SD condition can be
highly sensitive ELISA-based quantification (38). The expected to be identified in the future. These may include
non-invasive techniques facilitate larger clinical sam- the induction of endogenous anti-microbial materials
ple sizes thereby enhancing the quality of the data and such as β-defensins, which have been observed in vitro
allowing this approach to become routinely integrated as a result of Malassezia exposure (41) and in vivo in
in clinical evaluations. In the first use of this type of Malassezia-positive psoriasis (42) as well as the expres-
metho­dology on scalp to differentiate D/SD from nor- sion of Malassezia-related inflammatory mediators such
mal populations, the following inflammatory markers as malassezin (43). It is also possible that biomarker
were found to link accurately with the condition and quantifications associated with reactive oxygen species
other traditional parameters measured: IL-1ra (ratio to (ROS) defense will be identified, as there are indications
IL-1α), IL-2, IFN-γ, nitric oxide and TNF-α (39). that oxidative damage accompanies or causes D/SD.
Extensive clinical populations (using expert flake as- Therapeutic considerations. While these molecular
sessment to identify D/SD) have recently been evaluated level indications of D/SD increase the understanding of
(30, 40) for a wide range of molecular level biomarkers the pathological condition, they can also serve as new
comparing D/SD and normal populations. The data from measures to evaluate the therapeutic resolution of D/SD.
these two studies is re-plotted and represented in Fig. The data summarized from recent publications (30, 40)
2. Statistically significant differences were seen for the tracking the above biomarkers before and after treatment
two populations for all three inflammatory biomarkers with a commercial 1% potentiated ZPT shampoo are
investigated: IL-1ra/IL-1α, IL-8 and histamine. Structural re-plotted in Fig. 3. The data and statistical analysis are
biomarkers related to differentiation were also evaluated: based on change from baseline; normalization in some
the cell envelope protein involucrin showed only small cases requires some parameters to decrease while others
differences between the two populations (but is sensitive to increase. Significant reductions in all inflammatory
to response to treatment, see below) and the keratins 1, biomarkers quantified (IL-1ra/IL-1α, IL-8 and hista-
10 and 11 are substantially reduced in the D/SD popula- mine) were observed, showing a normalization of the
tion indicating incomplete terminal differentiation. Mo- skin inflammatory state (relative to the levels of these
lecular markers of barrier integrity were quantified that biomarker molecules observed in normal population,
completed the etiologic cascade: human serum albumin see Fig. 2). Likewise, both differentiation biomarkers
(HSA) and the epidermal intercellular lipids. Quantifica- were also significantly normalized: involucrin decreased
tion of HSA in the outer SC is a molecular measure of while terminal differentiation products keratins 1, 10
the decreased barrier integrity and function observed for and 11 increased. HSA also significantly decreased,
D/SD. Decreases in total ceramides and sphingoid bases indicative of the barrier function returning to normal
were observed for D/SD, supporting similar previous and consistent with structure/function level improve-

D/SD Population Normal population

Inflammation Differentiation Barrier integrity

6 0.8 0.6 30 16 16 3500 600
p<0.001 p<0.001 p<0.001 p<0.553 p<0.001 p<0.002 p<0.001 p<0.001

0.7 14 14 3000
5 0.5 25 500

0.6 12 12
2500
4 0.4 20 400
0.5 10 10
pg/µg protein

ng/µg protein
pg/µg protein

pg/µg protein
ng/µg protein

ng/µg protein

ng/µg protein
ng/µg protein

2000
3 0.4 0.3 15 8 8 300

1500
0.3 6 6
2 0.2 10 200
1000
0.2 4 4

1 0.1 5 100
0.1 2 2 500

0 0 0 0 0 0 0 0
IL-1ra/IL-1α IL-8 Histamine Involucrin Keratins Human Ceramides Sphingoid
1, 10, 11 Ser Alb Bases
Fig. 2. Summary of biomarker evaluations showing molecular level differentiation of D/SD and normal populations. Composite
representation of data (30, 40).

Acta Derm Venereol 93

 Dandruff and seborrheic dermatitis 135

Higher
200
* these correlations are all highly statistically
Better
significant, typically with p-values much
150 lower than 0.0001. If these statistical ana-
Percent Change from Baseline

lyses were done as averages by treatment

100 (rather than by person), thereby reducing
the person-to-person variability, correlation
*
50 * coefficients between individual biomarkers
and flake reduction are substantially higher
0 (often in the 0.7 range, data not shown).
This analysis demonstrates the significant
-50
*
correlation between individual biomar-
* * kers and the reduction in flakes as the key
Lower * *
Better
-100 symptom and current routine measure of
IL-1ra /
IL-1α
IL-8 Hista-
mine
Invo-
lucrin
Keratins
1,10,11
Human
Ser Alb
Cera- Sphingoid
mides Bases
the scalp condition. This both shows the
relevance of the biomarkers to the overall
Inflammation Differentiation Barrier Integrity
pathophysiological definition of the D/
Fig. 3. Summary of biomarker improvements upon D/SD treatment. Composite representation SD condition and also establishes them as
of data from (30, 40).
relevant surrogate measures for the clas-
sical clinical flake appearance reduction
ments observed (see above). Finally, intercellular lipids endpoint.
responsible for barrier function also increased signifi-
cantly, consistent with previous observations (37) and Discussion
supporting barrier function improvement.
Taken together, these molecular biomarker obser- Definition of a comprehensive pathophysiological
vations provide a further insight into the picture of description of dandruff and seborrheic dermatitis
the patho­physiology of the D/SD condition and offer The signs and symptoms of the D/SD conditions are
more detailed evidence of resolution with commerci- well established mainly through traditional (macro) as-
ally available treat­ments. While there is a consistency sessment of the scalp skin condition. The description of
between resolution of signs and symptoms of D/SD and the scalp condition at the structural and molecular level
the normalization of the biomarkers [22,32], we sought is now enabled by new molecular measurement capabi-
to assess the statistical significance of the correlations. lities. The pathophysiological model that is emerging
The commonly assessed variable of flake reduction as (Fig. 1) is based on the established etiological phases
quantified by the adherent scalp flake score (ASFS) of Malassezia metabolism initiating the inflammatory
(44) was used as the accepted clinical endpoint. This cascade, resulting in scalp skin hyper-proliferation and
was done (previously unpublished) by evaluating cor- incomplete corneocyte differentiation that yields an
relations as change from baseline on a person-by-person impaired SC barrier.
basis between the two parameters (a rigorous approach). Measures at the structure/function level, such as
Since this represents a correlation between two inde- epidermal morphology, Malassezia infiltration and
pendent in vivo measures, one depending on an expert instrumental assessments related to moisture content
grader (ASFS) and the other on an objective molecular have supported the basic etiology sequence discussed
technique (biomarker), including normal biological va- above. These measures have enabled a deeper under-
riability, low absolute correlations were expected. These standing of the pathophysiology of these conditions by
correlations are summarized for selected biomarkers in demonstrating that the superficial signs and symptoms
Table I, general ranges were ± 0.2, indicating the degree are the result of an irregular epidermal construction
of variability expected from these studies. However, and resultant dis-organization in the onset of D/SD.
These observations, in turn, have led to probing specific
Table I. Statistical correlation assessment (parametric) between molecular mechanisms in the skin, which established
selected biomarker and flaking changes from baseline on an the inflammatory nature of the condition, the poor syn­
individual basis
chronization of proliferation and differentiation and the
Biomarker (log10 ratio Observations Pearson correlation relatively ineffective barrier function.
Baseline:Treatment) n coefficient (r) p-value Rather than describing a healthy scalp as simply being
IL-1ra: IL-1α 1,960 0.2814 < 0.0001 free from signs and symptoms of a condition, these new
IL-8 1,966 0.2290 < 0.0001
Histamine 1,237 0.1038 = 0.0003
parameters enable both a more complete pathophysiolo-
Involucrin 1,964 0.2223 < 0.0001 gical description of D/SD as well as establishing more
Keratins 1,966 –0.2675 < 0.0001 specific criteria for assessing whether the condition has
Serum albumin 1,965 0.2563 < 0.0001 been effectively treated.

Acta Derm Venereol 93

136 J. R. Schwartz et al.
Additionally, these new D/SD measures support the
inclusion of D/SD in the broad group of inflammatory
dermatoses, including psoriasis, atopic dermatitis and
acne. These conditions have different triggering events,
but share the pathophysiology of inflammation, prolife-
ration and skin barrier impairment. Other inflammatory
dermatoses have been studied in more detail (45) than D/
SD; and the biomarker data reviewed here are especially
useful for demonstrating the commonalities of patho­
physiology with these well-established conditions (49).
Relevance of biomarkers as surrogate clinical measures
The benefits of developing a molecular, biomarker-
based quantification capability is likely to extend
beyond a more thorough understanding of a disease
condition and include the potential to use biomarkers
as relevant efficacy measures (46). If the biomarkers
reflect disease mechanisms underlying the clinical
pathophysiology, as they appear to in the case of D/
SD, they can be useful tools as measures earlier in the
onset of the condition, and/or as surrogate endpoints
for clinical efficacy of treatments. The FDA recognizes
this advantage of biomarker tools and encourages the
use of biomarkers in a recent white paper “Innova-
tion or Stagnation?” (47). An example of the use of
biomarker analysis in dermatology exists for atopic
dermatitis (AD) (48). Surface quantification of IL-18
was found to correlate with the severity of the condi-
tion and appeared to be due to Staphylococcus aureus
colonization. This is an example demonstrating both
benefits of this biomarker for AD: generation of new
pathophysiological information and the establishment
of a new clinical measurement endpoint.
A number of biomarkers have been found to be
significantly correlated to the key D/SD symptom of
flaking (see Table I), even when evaluated on the basis
of individuals analyzed. All of these biomarkers have
a specific rationale within the known etiology of the
condition, enabling a greater, more detailed understan-
ding of the pathophysiology of D/SD. These biomarkers
can also be used as surrogate clinical endpoints for the
detailed assessment of D/SD treatment success, thus
complementing the traditional measures that are mainly
focused on visible signs/symptoms.
Future directions
The new capabilities of measuring the state of the scalp
skin physiology with biomolecular markers facilitate a
greater understanding of pathophysiology of the D/SD
condition. New non-invasive measures will continue
to be developed in the future that can shed more light
on interactions between Malassezia and the epidermis.
There is still much to learn, for example, why does D/
SD of the scalp require a physical covering of hair?
Another critical question is why a commensal orga-
Acta Derm Venereol 93
nism such as Malassezia triggers D/SD in some but
not others.
ACKNOWLEDGEMENT
Conflicts of interest: This work was funded by Procter & Gam-
ble. JRS, KMK, JPH, RCR and MKR are employees of Procter
& Gamble. AGM, AT, GT, MH, RJH and XW were provided an
honorarium for their expert contributions.
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